Treatment Therapies

Current therapy - Erlotinib

Targeting HER1/EGFR

There are several potential mechanisms for inhibiting HER1/EGFR activity (Figure 1)¹ and these can be classified as follows:

Prevention of ligand binding to the extracellular domain of the receptor.
Inhibition of the TK activity.
Exploitation of the ligand-receptor specificity to target toxins to the tumour.

Potential strategies for targeting HER1/EGFR signalling

Figure 1. Potential strategies for targeting HER1/EGFR signalling.

Prevention of ligand binding

One of the most efficient ways to inhibit ligand binding and receptor activation is by using specific monoclonal antibodies (MAbs) that have been raised against the extracellular domain of HER1/EGFR. Some MAbs are now approved for marketing in certain territories and several others are currently in clinical development.

IMC-C225, cetuximab (Erbitux^®, Imclone, Merck KGaA). Cetuximab is a chimeric human-mouse IgG1MAb that binds to the extracellular domain of HER1/EGFR thereby inhibiting ligand binding.This action blocks EGF-induced autophosphorylation of HER1/EGFR and promotes down-regulation by receptor internalisation.² In-vitro studies have shown that cetuximab inhibits proliferation by arresting cells in the G1 phase of the cell cycle, and this is accompanied by increases in the levels of p27kip1, an inhibitor of cyclin-dependent kinases.³ Other in-vitro studies have indicated that cetuximab in combination with cytotoxic agents such as doxorubicin, cisplatin, paclitaxel, gemcitabine, and topotecan can induce tumour-growth inhibition or regression, and increase sensitivity to radiation.⁴

Cetuximab has shown clear clinical efficacy against colorectal cancer⁵ and has been approved for marketing in the USA and Europe for patients with metastatic colorectal cancer that has progressed whilst receiving irinotecan therapy. Clinical phase III studies are currently underway to evaluate the addition of cetuximab to folinic acid (FA)/5-FU/oxaliplatin (FOLFOX) or FA/5-FU/irinotecan (FOLFIRI) in colorectal cancer.^6,7 A further phase III trial has shown that cetuximab plus radiotherapy significantly improves 2- and 3-year survival in patients with advanced HNSCC compared with radiotherapy alone.⁸ The activity of cetuximab in NSCLC is also under investigation.⁹

Other monoclonal antibodies targeted against HER1/EGFR. ABX-EGF (panitumumab, Abgenix), EMD-72000 (matuzumab, Merck KGaA), and hR3 (York Medical BioSciences) all bind to the extracellular domain of HER1/EGFR and inhibit ligand binding and autophosphorylation.⁴ ABX-EGF is currently in phase II development in combination with paclitaxel and carboplatin for the treatment of NSCLC52 and as a monotherapy for metastatic colorectal cancer.¹⁰EMD-72000 is currently in phase II development.

Inhibition of TK activity

The other major approach to inhibiting the HER1/EGFR signalling pathway is to use a molecule that acts directly as a TKI. In general, the small-molecule TKIs bind reversibly to the catalytic TK domain of HER1/EGFR where they compete with the binding of ATP and, therefore, inhibit autophosphorylation and activation. The TKIs in current clinical development belong to one of three chemical classes; 4-anilinoquinazolines, 4-[ar(alk)ylamino] pyridopyrimidines, and 4-phenylaminopyrrolo-pyrimidines. The TKIs can be differentiated on the basis of receptor affinity, bioavailability and potency for inhibiting phosphorylation.¹¹The small molecule TKIs are orally available, which makes them more convenient for use compared with MAbs that need to be administered by infusion.

OSI-774, erlotinib (Tarceva^TM, F. Hoffmann-La Roche Inc./ Genentech/OSI Pharmaceuticals). Tarceva^TM belongs to the 4-anilinoquinazoline class of HER1/EGFR TKIs. As a result of its inhibitory action, Tarceva^TM selectively and reversibly inhibits the TK activity of HER1/EGFR (Figure 2), which affects many downstream processes leading to a block in G1 of the cell cycle and an accumulation of the cell cycle inhibitor p27kip1. Tarceva^TM also induces apoptosis in cultured cells and inhibits tumour growth in human xenograft tumour models in nude mice with no major toxicity.^12,13

TarcevaTM-mediated inhibition of HER1/EGFR activation

Figure 2. Tarceva^TM-mediated inhibition of HER1/EGFR activation.

ZD1839, gefitinib (Iressa^®, AstraZeneca). Like Tarceva^TM, gefitinib is an orally available quinazoline derivative, and also selectively and reversibly inhibits the TK activity of HER1/EGFR.¹⁴ As a consequence, many of the intracellular effects of gefitinib are similar to those of Tarceva^TM.
Other small molecule (TKIs). There are several other TKIs in early clinical development. PD-183805 and its orally available water-soluble derivative CI-1033 (canertinib, Pfizer) are irreversible TKIs with activity against HER1/EGFR, HER2 and HER4. The biological mode of action is similar to gefitinib and Tarceva™ in that they act by inhibiting ligandmediated activation of the AKT and MAPK signalling pathways to enhance the efficacy of traditional cytotoxic drugs and radiation. PKI-166 (Novartis) is a reversible inhibitor of HER1/EGFR TK and GW572016 (lapatinib, GlaxoSmithKline) acts against both HER1/EGFR and HER2. Both have shown antitumour activity in vitro that is consistent with inhibition of the HER1/EGFR signalling pathway (reviewed in Ciardiello and Tortora 2002).⁴

Exploiting the specificity of the ligand-receptor interaction

There are several related strategies that aim to exploit the specificity of the ligand-receptor interaction and such approaches also have therapeutic potential. One such approach uses a recombinant form of human EGF which is linked to the highly immunogenic recombinant protein P64k (EGF-P64k). Bispecific antibodies (e.g. MDX-447 and H22-EGF, both manufactured by Medarex) are engineered to bind to the HER1/EGFR extracellular domain and a specific molecule on the surface of a cell of the host immune system (e.g. CD64 which is found on both monocytes and neutrophils). This results in both an inhibition of signalling through HER1/EGFR and enhances the natural immuno-cytotoxicity of the body. Phase I studies of MDX-447 have shown promising results and phase II studies are ongoing.¹⁴

References:
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